Patient-derived cancer organoids to tailor personalized treatment strategies in upper gastrointestinal malignancies

Abstract

Summary Upper gastrointestinal malignancies bear a high morbidity and mortality burden. Curative treatment requires a multimodal approach, subjecting patients to preoperative chemotherapy or chemoradiation to downstage the tumor before resection. Various preoperative regimens exist but there is no tailor-made approach based on the tumor sensitivity for the individual patient. This predisposes a considerable subset of patients to inadequate treatment and highlights the need for personalized medicine, for which the potential of patient-derived cancer organoids (PDCOs) was investigated. PDCOs were established from pre-treatment biopsies of two gastric and four esophageal cancer patients, and compared to previously established PDCOs derived from four gastric and two esophageal resections post-neoadjuvant treatment. PDCO sensitivity, defined as area under the dose–response curve, was determined to in vitro chemotherapy (epirubicin, oxaliplatin, capecitabine and 5-fluorouracil, leucovorin, oxaliplatin, docetaxel) and chemoradiation (carboplatin, paclitaxel, radiotherapy). The PDCOs were established from 55% of the pre-treatment biopsies (derived from four of six patients), and demonstrated differential sensitivity to the treatment screens. PDCOs initiated from pre-treatment tissue were more sensitive than those derived from post-treatment tissue. In addition, drug screen sensitivity of pre-treatment PDCOs correlated well with patient response in terms of tumor regression grade. The current results provide a proof of principle and offer recommendations for a structured pipeline to more efficiently establish, validate and screen a larger cohort of pre-treatment PDCOs.